Field of the Invention
The present invention is generally directed to novel compounds having activity as inhibitors of ALK2 and/or JAK2 kinases and use of the same for treatment of various cancers.
Description of the Related Art
The Janus kinases (JAKs) are a family of kinases of which there are four in mammals (JAK1, JAK2, JAK3 and TYK2) that are integral in signaling from extracellular cytokines, including the interleukins, interferons, as well as numerous hormones (Aringer, M., et al., Life Sci, 1999. 64(24): p. 2173-86; Briscoe, J., et al., Philos Trans R Soc Lond B Biol Sci, 1996. 351(1336): p. 167-71; Ihle, J. N., Semin Immunol, 1995. 7(4): p. 247-54; Ihle, J. N., Philos Trans R Soc Lond B Biol Sci, 1996. 351(1336): p. 159-66; Firmbach-Kraft, I., et al., Oncogene, 1990. 5(9): p. 1329-36; Harpur, A. G., et al., Oncogene, 1992. 7(7): p. 1347-53; Rane, S. G. and E. P. Reddy, Oncogene, 1994. 9(8): p. 2415-23; Wilks, A. F., Methods Enzymol, 1991. 200: p. 533-46). These non-receptor tyrosine kinases associate with various cytokine receptors and act to transduce the signal from extracellular ligand-receptor binding into the cytoplasm, by phosphorylating STAT (signal transducer and activator of transcription) molecules, which then enter the nucleus and direct transcription of various target genes involved in growth and proliferation (Briscoe, J., et al.; Ihle, J. N. (1995); Ihle, J. N. (1996); Rawlings, J. S., K. M. Rosier and D. A. Harrison, J Cell Sci, 2004. 117(Pt 8): p. 1281-3.). The four JAK isoforms transduce different signals by being associated specifically with certain cytokine receptors, and activating a subset of downstream genes. For example, JAK2 associates with cytokine receptors specific for interleukin-3 (Silvennoinen, O., et al., Proc Natl Acad Sci USA, 1993. 90(18): p. 8429-33), erythropoietin (Witthuhn, B. A., et al., Cell, 1993. 74(2): p. 227-36), granulocyte colony stimulating factor (Nicholson, S. E., et al., Proc Natl Acad Sci USA, 1994. 91(8): p. 2985-8), and growth hormone (Argetsinger, L. S., et al., Cell, 1993. 74(2): p. 237-44).
The JAK family of enzymes has become a set of targets for various hematological and immunological disorders. JAK2 is currently under study as a viable target for neoplastic disease, especially leukemias and lymphomas (Benekli, M., et al., Blood, 2003. 101(8): p. 2940-54; Peeters, P., et al., Blood, 1997. 90(7): p. 2535-40; Reiter, A., et al., Cancer Res, 2005. 65(7): p. 2662-7; Takemoto, S., et al., Proc Natl Acad Sci USA, 1997. 94(25): p. 13897-902) as well as solid tumors (Walz, C., et al., J Biol Chem, 2006. 281(26): p. 18177-83), and other myeloproliferative disorders such as polycythemia vera (Baxter, E. J., et al., Lancet, 2005. 365(9464): p. 1054-61; James, C., et al., Nature, 2005. 434(7037): p. 1144-8; Levine, R. L., et al., Cancer Cell, 2005. 7(4): p. 387-97; Shannon, K. and R. A. Van Etten, Cancer Cell, 2005. 7(4): p. 291-3), due to its activation of downstream effector genes involved in proliferation. Because of its association with, and deregulation in, neoplastic and myeloproliferative disorders, small molecule JAK2 inhibitors for the treatment of human malignancies are of significant interest.
Bone morphogenetic proteins (BMPs) are pleiotropic growth factors playing essential roles in coordinating tissue architecture throughout various organs in the body. BMP ligands interact with bone morphogenetic protein receptors (BMPRs), which belong to the transforming growth factor beta (TGF-b) superfamily of serine/threonine kinase receptors (Ikushima, H. and K. Miyazono, Biology of Transforming Growth Factor-beta Signalin. Curr Pharm Biotechnol, 2011). The ligands bind to type-II receptors, which then recruit type-I receptors forming a heteromeric complex. As a complex, the type-II receptor phosphorylates the type-I receptor, which allows the type-I receptor to become active and phosphorylate downstream signaling molecules. The downstream effects of activating these receptors are primarily carried out by the SMAD family of proteins. SMADs become phosporylated and transduce the signal from the cell membrane to the nucleus where they function as transcription factors to regulated gene expression (Massague, J., J. Seoane, and D. Wotton, Smad transcription factors. Genes Dev, 2005. 19(23): p. 2783-810).
In individuals with chronic diseases, such as cancer and inflammation, BMP signaling is constitutively activated leading to anemia. This condition is commonly referred to as anemia of chronic disease (ACD) and is a debilitating symptom associated with cancer patients (Cullis, J. O., Diagnosis and management of anaemia of chronic disease: current status. Br J Haematol, 2011. 154(3): p. 289-300). Chronic anemia in cancer patients leads to extreme weakness and fatigue, which leads to a poor quality of life for these individuals. In these patients, BMP signaling through two BMP type-I receptors, ALK2 (also known as ACVR1) and ALK3 induces the hepatic expression of the peptide hormone, called hepcidin (Steinbicker, A. U., et al., Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice. Blood, 2011. 118(15): p. 4224-30). Hepcidin reduces serum iron levels by promoting the degradation of the iron exporter, ferroportin, resulting in the increase of iron stored away in macrophages and other cell types and making the iron unavailable for hemoglobin and red blood cell (RBC) function. Supplementing a patient's intake of iron does not reverse ACD because the ingested iron simply is stored away due to the activated BMP pathway and high serum hepcidin levels. Currently, ACD in cancer is managed by limiting the physical activity of patients and blood transfusions are used in the most severe cases Inhibition of BMP signaling in these patients has the potential to provide a real difference in their quality of life and ultimately, may positively impact how they respond to therapy, radiation, or surgery (Steinbicker, A. U., et al., Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood, 2011. 117(18): p. 4915-23; Coyne, D. W., Hepcidin: clinical utility as a diagnostic tool and therapeutic target. Kidney Int, 2011. 80(3): p. 240-4; Theurl, I., et al., Pharmacologic inhibition of hepcidin expression reverses anemia of chronic disease in rats. Blood, 2011).
In addition to its function in ACD, BMP signaling plays pivotal roles in the growth and metastasis of cancer cells, particularly in breast, prostate, and other cancers that frequently metastasize to the bone (Ye, L., M. D. Mason, and W. G. Jiang, Bone morphogenetic protein and bone metastasis, implication and therapeutic potential. Front Biosci, 2011. 16: p. 865-97). BMPs and BMPRs are more highly expressed in metastatic breast cancer cells compared to less metastatic ones and also in prostate cancer cells that generate osteosclerotic bone metastases (Bobinac, D., et al., Expression of bone morphogenetic proteins in human metastatic prostate and breast cancer. Croat Med J, 2005. 46(3): p. 389-96). In addition to effecting the invasiveness and metastasis of cancer cells, the BMP pathway has also been shown to influence the bone microenvironment. The cross-communication between cancer cells and the bone microenvironment via the BMP signaling pathway promotes the metastasis of the cancer cells to the bone. Studies have shown that the inhibition of BMP signaling significantly reduces bone tumor burden and osteolytic disease in a preclinical model of prostate cancer bone metastasis. These results suggest that a BMP inhibitor may have application in preventing bone metastases in addition to its activity against anemia induced by chronic disease.
Furthermore, a BMP inhibitor has the potential to treat multiple disease indications outside of cancer. ACD is a devastating condition that affects individuals suffering from other diseases, including rheumatoid arthritis, systemic lupus, chronic kidney disease, and many other inflammatory diseases. Additionally, a rare childhood genetic disease, called fibrodysplasia ossificans progressive (FOP) has been shown to be caused by activating mutations in the alk2 gene (Kaplan, F. S., et al., Investigations of activated ACVR1/ALK2, a bone morphogenetic protein type I receptor, that causes fibrodysplasia ossificans progressiva. Methods Enzymol, 2010. 484: p. 357-73). The mutation in ALK2 in this disease causes fibrous tissue (muscle, tendon, ligament, etc.) to be ossified when damaged. In other words, when patients with this condition experience injury to muscle or joint tissues, the repaired tissue is converted to bone causing joints to be permanently frozen in place. By the teenage years, these children have lost most of the function of their joints. Studies performed in animal models of FOP suggest that inhibiting ALK2 decreases the “flare-ups” associated with FOP and prevents the ossification of repaired tissue in the model. The medical and commercial benefits of a BMP inhibitor (i.e. ALK2) are quite broad and extend to multiple indications outside of cancer.
While progress has been made in this field, there is a need for the design of specific and selective inhibitors for the treatment of cancer and other conditions that are mediated and/or associated with ALK2 and/or JAK2 (including JAK2 V617F) protein kinases. The present invention fulfills these needs and offers other related advantages.